Atrial fibrillation (AF), a common cardiac arrhythmia, affects >2 million Americans and is associated with increased morbidity, mortality, and healthcare costs. Adequate antithrombotic treatment in AF is critical to preventing stroke and other complications. To date, this has been mostly achieved with vitamin K antagonists (warfarin in the US). Warfarin use, however, is burdensome and carries a significant risk of complications. Recently, new oral anticoagulants (OACs; dabigatran, rivaroxaban, apixaban) have proved in randomized trials to be at least as efficacious as warfarin in preventing stroke in AF patients. Randomized trials, however, are not always generalizable to the usual clinical setting. Therefore, additional research is necessary to determine the effectiveness of these new OACs, compared to warfarin, and to identify patients more likely to benefit from the new medications. In this application, we propose to assess the following specific aims: (1) to estimate the effectiveness of new OACs versus warfarin treatment in the prevention of ischemic stroke, systemic embolism, healthcare utilization, and mortality;(2) to assess the risk of bleeding and other complications (myocardial infarction, dyspepsia) associated with use of new OACs versus warfarin in these patients; (3) to identify patient subgroups, defined by age, sex, race/ethnicity, comorbidities, and use of other medications, for which the new OACs are particularly beneficial or hazardous; and (4) to develop and validate risk predictive models of stroke / cardioembolic complications and severe hemorrhage in AF patients using new OACs. To address these research questions, we will use two large claim databases, OptumInsight and MarketScan. These databases include health insurance claims from over 1 million patients with AF, and >155,000 users of new OACs. State- of-the-art methods for comparative effectiveness research, including high-dimensional propensity scores, marginal structural models, and instrumental variables, will be used to adjust for confounding. Results from our research will provide key evidence to help patients and clinicians make decisions about their anticoagulant treatment, balancing benefits and risks associated with different therapeutic options. This proposal also has the potential to inform decisions by regulatory agencies, insurers, health system leaders, and professional organizations in issues such as post marketing approval, reimbursements, and clinical guidelines.